Substituted derivatives of saturated or unsaturated pregnanediones



Patented Feb. 2, 1943 UNHTED SATES FATE SUBSTITUTED DERIVATIVES OF SATU-RATED OR UNSATURATED PREGNANE- DIONES No Drawing. Application May .13,1940, Serial No. 334,988

21 Claims.

This invention is a further development of the inventions described andclaimed in my copending applications Ser. Nr. 195,161, filed March 10,1938, Ser. Nr. 195,162,.filed March 10, 1938, and Ser, Nr. 255,483,filed February 9, 1939, as a division of the aforesaid application Ser.No. 195,161, and relates to 3.20-diketones of the saturated andunsaturated pregnane series carrying a substituent at the C21 carbonatom and which may-further carry additional substituents in the ringsystem, all as more fully described hereinafter. I

In my applications Ser. Nr. 195,161 and Ser. Nr. 255,483 a process wasdescribed and claimed whereby saturated or unsaturated etiocholanicacids, which might contain further substituents in the ring system,especially oxygen in different forms of combination, were converted intothe corresponding diazo-21-pregnaneones-20. In particular the productionof such derivatives as bear a free hydroxyl group at the carbon atom C3was described. The general formula of such compounds is given by formulaI CH3 CH3 i c CHNz I X=holagen, OH, O-alkyl, O-aralkyl, O-acyl, =0

a=an integer or zero The ring system may contain one or more doublebonds In these diazo compounds the COCHN2 group was immediatelysubjected to further treatment to convert it into a COCHzR group,wherein R indicates halogen, hydroxyl, acyloxyl or alkoxyl.

In my application Ser. Nr. 195,162 I described a process for oxidizingthe 3-hydroxyl group in the compounds with a COCHZR group so formed to aketo group, whereby saturated or unsaturated derivatives ofpregnanedione-3.20 are produced. The said conversion of the COCHNz groupinto a COCI-IzR group Was effected at an early stage of the processbecause it was thought desirable to transform the diazo group as soon aspossible into a group, which is known to be stable to varioustreatments. It is well known in the art that aliphatic diazo compoundsare generally extremely unstable.

Surprisingly, however, I have now found that may be added to thereaction mixture.

it is possible to oxidize to a keto group the 3- hydroxyl group in thesaid diazo compounds without decomposition of the diazo group. In thisWay the diazo-21-diketo-3,20-derivatives of the general formula II areobtained CH3 CH3 In the preferred embodiment of this process I efiectthe oxidation with an excess of a carbonyl compound as the oxidizingagent in the presence of a metal alcoholate. An inert solvent Theoxidation can either be efiected at room temperature or atelevatedtemperatures, e. g. at the boiling pointof the reaction mixture. In theformer case the time required to complete the-reaction will evidentlyhave to be prolonged.

The diazo-'21-pregnane-diones-3.20 which are obtained by the oxidationcan be subjected to the action of acids, whereby the diazo group may beconverted into various other groups. For example by treatment with.hydrogen halides in substantially anhydrous solution the 21-diazocompounds are converted into the 2'1-ha1ogen compounds. Upon-reaction ofthe diazo compounds with dilute aqueous solutions of inorganic oxygenousacids or oforganic sulphonic acids the diazo group is hydrolysed to ahydroxyl group. By treatment with an organic carboxylic acid in theabsence of water, derivatives with an acyloxyl group at the carbon atomC21 are obtained.

, Moreover, by treatment'with anhydrous inorganic-'oxygenous acids in asuitable solvent, inorganic 21-esters can be obtained. If the inorganicoxygenous acid is polybasic, the esters so formed are capable of formingwater soluble salts which are suitable for intravenous injection.

Various substituents, such as halogen, hydroxyl, alkoxyl, aralkoxyl,acyloxyl and keto groups, may be present in the ring system, which mayalso contain one or more double bonds. All this is without influence onthe course of the reaction. If, apart from the hydroxyl group, at thecarbon atom C3, other secondary hydroxyl groups are present they may,however, also be oxidized to a keto group. Special advantages of myprocess are that pregnane-diones-3.20 is formed. If an inorganicpolybasic oxygenous with various substituents at the carbon atom acid isused the ester with desoxycorticosterone C21 can now be obtaineddirectly, e. g. there is will have acidic properties and may beconverted no longer any need for protection of a hydroxyl into a salt.

III I/ IV V CH3 CH3 .1 CH3 on; om on;

tC.OCHzOH T-ooomosm l-c0011 1 01 VI VII VIII group, if present, at C21,as in the process de- Example 1 scribed in my application Ser. Nr.195,162. Further the production of various ZI-substituted pregnanediones-3.20 is simplified; the processes for obtaining these variouscompounds now run parallel until the stage of the diazo-21-diketo- 3.20compounds.

Moreover, the yields obtainedby thenew process compare inmost casesveryfavorably with those of processes-formerly known. So the conversionof the diazo zlepregnane-diones with anhydrous organic-acids givesalmost quantitatlveylelfi' Since also the. voxtdatlon gwes 3' a smallquantity .of dry ether was added, after cellentyields, the all-overy1eld'm theproduction which crystallisation occurred immediately. The ofthe 21-subst1tutecl pregnane-diones from the Crystals were Washed withether Thp diazo 'corrtesponding. hydroxy'g'fetiocholamc acids isprogesterone obtained melted 182:184 0. conslderably hlgher than informer processes (corrected) under decomposition. The yield was 200 mg.of diazo-2l-pregnene-5-ol-3-one-20. 500 mg. of aluminium tertiarybutylate, 20 cc. of dry benzene and 6 cc. of acetone were mixed in aglass tube, which was sealed and allowed to stand at room temperature,for 20 days. Thereupon the mixture was diluted with ether, washed insuccession with solutions of 'Seignette-salt, and of sodium carbonateand with water. The ethereal solution was dried withsodium sulphate,whereupon the ether was evaporated, first on a water bath and finally invacuo. To the residue A further :advantage is that the diazo-Zl- 136 Thecompound i very slightly soluble dlketo's'zfl COmDQImdS in ether,moderatel soluble in acetone and easily s fi are excellentlyWStamzmsoluble in benzene. The crystals are of a light stances, WhlChconsiderably facilitates thepuriyellow Colour fi-cation of same. 5Example 2 The products obtained by my process are therapeuticallyvaluable or "may serve as vinter- 60 g. o diam- -pregnene5-0l-3-one-20are mediates for the production of therapeuticals. dissolved in 2200 cc.of thiophene-free dry ben- In order to make the process more clear ex-Zo e and 1 0 0- O acetOne P v o s y distilled amples and formulaefor thereactions involved Over potassium permanganate 150 Of uwill be given.For the sake'of simplicity asimminium tertiary b y are dded. The mixple.case will be discussed, viz. the production ture is heated to 68-70"under stirring for 7 of derivatives of pregnene-4-ol-2l-dione--3.20hours. After cooling the solution is extracted (desoxycorticosterone).It is to be understood, w e W 500 0- o s ette-sa t solution however,that my invention'isnot limitedto these and Subsequently washed twicewith 40 0 cc. of examples but may be varied within the scope of 5%sodium carbonate solution and four times the appended claims. withwater. The washings are extracted twice For example one starts with diaz-21-preg- With benzene. The benzene solutions are 00111,-nene-5-ol-3-one-20 (III) which is oxidized to bined and dried w um suphat After diazosprogesterone v From th w t hydrofiltering oil thesodium sulphate the benzene is gen halides the halogen-dione (V) isformed. evaporated in va u at 50 C- When no more By hydrolysis of IVwith the aid of .aqueous-soluliquid d t lls 300 cc. of dry ether areadded to tions of inorganic oxygenous acids'or of organic e e- After stag for 10 hours at 5 sulphonic .acids desoxycorticosterone (VI) is C- they fi y grained -p e formed; by treatment of IV with substantially one isfiltered by Suction, Washed W y ether anhydrous :organic carboxylicacids the carand dried at C- The yield is 42 t {1800mboxylic acid estersof desoxycorticosterone (VII) D ses at 5- 80". are formed. Finally, byreacting IV with an in- Example 3 organic .oxygenous acid an inorganicester of desoxycorticosterone, e. g. the phosphate (VIII), .20 .mgofdiazo-21-pr r ne w r mix d with a solution. of 0.2 g. of dry gaseoushydrochloric acid in 3 cc. of dry ether. The crystals quickly dissolvedunder evolution of nitrogen. After 3 minutes the solution was dilutedwith a small quantity of ether and washed with water, sodium carbonatesolution and again with water. The ethereal solution was dried withsodium sulphate and evaporated to a small volume, whereupon colourlesscrystals separated which were washed with a small quantity of ether. Thesubstance melted at 201-204" (corrected) and showed to be identical withchloro-2l-progesterone (mixed melting point). The yield was 14 mg.

Example. 4

2 g. of diazo-21-progesterone are dissolved in 28 cc. of dioxane ofpurest quality. 21 cc. of 2 N sulfuric acid are added. A slightevolution of nitrogen sets in at room temperature; it ceases afterheating to 40 C, during 15 minutes. The reaction mixture is poured into400 cc..of water, the mixture is extracted twice with 200 cc. of ether.The ethereal solution is washed three times with 5% sodium carbonatesolution and three times with water and subsequently dried with sodiumsulphate. After filteringoff the sodium sulphate the ethereal solutionis evaporated to a small volume. 1.54 g. of desoxycorticosteronecrystallize. Melting point 132-138 C. After recrystallizing once fromether 1.44 g. are obtained with melting point 137-140 7 Example 5 ittwice with 250 cc. of 5% sodium carbonate Example 6 l 9.5 g. of diazo-2lprogesterone and 23 g. of benzoic acid are dissolved in cc. of toluene.Upon heating on a water bath a vigorous evolution of nitrogen sets in.at 80 C. which stops, when the temperature has been raised to 90 C.after about 20 minutes. After cooling the re-- action mixture is dilutedwith 200 cc. of ether and washed out with 400 cc. of water, three timeswith 250 cc. of 5% sodium carbonate solution and then again three timeswith 250 cc. of water. After drying with sodium sulphate and filteringthe ether and the toluene are distilled off. The residue is crystallizedfrom cc. of acetone. 8 g. of desoxycorticosterone benzoate are obtained.After repeated recrystallization from an acetone water mixture themelting point is 206 408 C. (a)n=+204.

Example 7 Diazo-21-progesterone is gently heated in dioxane with thecalculated quantity of anhydrous phosphoric acid. At a temperature of4550 C. the reaction is completed in about 10 minutes. The reactionmixture is evaporated in a high vacuo, the residue is mixed with waterand thereafter the desoxycorticosterone phosphate obtained is extractedwith ethyl acetate. The extract is washed with water and evaporated invacuo. The residue is dissolved in methanol, after which exactly thecalculated quantity of sodium methylate is added. The solution has aslightly alkaline reaction towards litmus. It is first evaporated invacuo, the residue is dried and again dissolved in methanol, whereuponany insoluble substances are separated by filtration. The solutionobtained is again evaporated to a small volume, whereafter the reactionproduct is precipitated by acetone. The sodium salt ofdesoxyvorticosterone phosphate obtained is washed with acetone andether. It is easily soluble in water and upon analysis shows thecalculated phosphorus content.

What I claim is: w

1. The process which comprises converting to a keto group the 3-hydroxylgroup in a compound having'the empirical formula XaC21H32c-2bO2N2land'the structural formula on; on;

in which X indicates substituents in the ring system selected from thegroup consisting of halogen, hydroxyl, alkoxyl, aralkoxyl, acyloxyl, andketo groups; a denotes a number from the group of zero and an integer; bis a number from the group of zero and an integer which denotes thenumber of double bonds in the ring system, and 0 denotes the number ofhydrogen atoms substituted by mild oxidation in the presenee of aluminumtertiary butylate.

2. The process which comprises oxidizing to a'keto group the 3-hydroxylgroup in a compound having the empirical formula and the structuralformula CH3 CH:

l lCOCHNz I/\/\/ H0 in which X indicates substituents in the ring systemselected from the group consisting of halogen, hydroxyl, alkoxyl,aralkoxyl, acyloxyl and keto groups; a denotes a number from the groupof zero and an integer; b is a number from the group of zero and aninteger which denotes the number of double bonds in the ring system, andc denotes the number of hydrogen atoms substituted; whereupon theoxidation product is subjected to the action of anacid,

and further characterized in that the oxidation is effected with anexcess of a carbonyl compound in the presence of aluminum tertiarybutylate. v

3. The process which comprises oxidizing to a keto group the B-hydroxylgroup in a compound having the empirical formula and the structuralformula om om I i i HO in which X indicates substituents in the ringsystem selected from the group consisting of halogen, hydroxyl, alkoxyl,aralkoxyl, acyloxyl and keto groups; a denotes a number from the groupof zero and an integer and denotes the number of hydrogen atomssubstituted; and further characterized in that the oxidation is effectedwith an excess of a carbonyl compound in the presence of tertiaryaluminum butylate.

4. The process which comprises converting. by mild oxidation in thepresence of aluminum tertiary butylate, to a keto group the S-hydroxylgroup in a compound having the empirical formula XaC21H30cO2N2 and thestructural formula CH3 CH3 A --o 0 011m and the structural formula CH3om -oooHN in which X indicates substituents in the ring system selectedfrom the group consisting of halogen, hydroxyl, alkoxyl, aralkoxyl,acyloxyl and keto groups; (1 denotes a number from the group of zero andan integer and c denotesthe number of hydrogen atoms substituted;whereupon the oxidation .product is subjected to the action of an acidand further characterized in that the oxidation is effected with anexcess of a carbonyl compound in the presence of aluminum tertiarybutylate. v

6. The process which comprises converting'to a keto group the 3-hydroxy1group in diazo-2L- pregnene-5-ol-3-one-20 by mild oxidation in thepresence of aluminum tertiary butylate.

7. The process which comprises oxidizing to a keto group the 3-hydroxylgroup in diazo-21 pregnene-5-ol-3-one-20 by treatment with an excess ofa carbonyl compound in the presence of aluminum tertiary butylate.

8. The process which comprises converting to a keto group the 3-hydroxylgroup in diazo-'21- pregnene-5-ol-3-one-20 by mild oxidation in thepresence of aluminum tertiary butylate, whereupon the diazo progesteroneobtained is subjected to the action of an acid.

9. The process which comprises oxidizing to a keto group the 3-hydroxylgroup 'in diazo-21- pregnene-5-ol-3-one-20 by treatment with an excessof a carbonyl compound in the presence of aluminum tertiary butylate,whereupon the diazo progesterone obtained is subjected to the action ofan acid.

10. A process for the preparation of desoxycorticosterone whichcomprises oxidizing to a keto 'group the 3-hydroxyl group in diazo-21pregnene-5-ol-3-one-20 by treatment with an excess of a carbonylcompound in the presence of aluminum tertiary butylate, whereupon thediazo progesterone obtained is hydrolysed. I

11. A process for the preparation of'carboxylic acid esters ofdesoxycorticosterone, which comprises oxidizing to a'keto group the3-hydroxy1 group in diazo-21-pregnene-5-ol 3-one-20 by treatment with anexcess of a carbonyl compound in the presence of aluminum tertiarybutylate,'whereupon the diazo progesterone obtained is treated with anorganic carboxylic acid under substantially anhydrous conditions.

12. A process for the preparation of inorganic acid esters ofdesoxycorticosterone, which comprises oxidizing to a keto group the3-hydroxyl group in diazo-2l-pregnene-5-ol-3-one-2O by treatment with anexcess of a carbonyl compound in the presence of aluminum tertiarybutylate, whereupon the diazo progesterone obtained is treated with aninorganic acid under substantially anhydrous conditions.

13. A process for the preparation of esters of desoxycorticosterone witha polybasic oxygenous inorganic acid, which comprises oxidizing to aketo group the 3-hydroxyl group in diazo-21- pregnene-5-ol-3-one-2O bytreatment with an excess of a carbonyl compound in the presence ofaluminum tertiary butylate, whereupon the diazo progesterone obtained istreated with a polybasic oxygenous inorganic acid under substantiallyanhydrous conditions.

14. A process for the preparation of salts of esters ofdesoxycorticosterone with a polybasic oxygenous inorganic acid, whichcomprises oxidizing to a keto group the 3-hydroxyl group indiazo-21-pregnene-5-ol-3-one-20 by treatment with an excess of acarbonyl compound in the presence of aluminum tertiary butylate,whereupon the diazo progesterone obtained is treated with a polybasicoxygenous inorganic acid under substantially anhydrous conditions andthe acid ester so formed is further converted into a salt.

15. A process for the preparation of phosphoric acid esters ofdesoxycorticosterone, which comprises oxidizing to a keto group the3-hydroxyl group in diazo-21-pregnene-5-ol-3-one-20 by treatment with anexcess of a carbonyl compound in the presence of aluminum tertiarybutylate, whereupon the diazo progesterone obtained is treated with aphosphoric acid under substantially anhydrous conditions.

16. A process for the preparation of salts of phosphoric acid esters ofdesoxycortioosterone, which comprises oxidizing to a keto group the3-hydroxy1 group in diazo-21-pregnene-5-ol-3- one-20 by treatment withan excess of a carbonyl compound in the presence of aluminum tertiarybutylate, whereupon the diazo progesterone obtained is treated with aphosphoric acid under substantially anhydrous conditions and thedesoxycorticosterone phosphate so formed is further converted into asalt.

1'7. A compound of the group consisting of the phosphoric acid esters ofdesoxycorticosterone and the salts thereof.

18. The sodium salts of phosphoric acid esters of desoxycorticosterone.

19. The sodium salt of desoxycorticosterone orthophosphate.

20. Process for preparing derivatives of the saturated and unsaturatedpregnane series having a 3-position keto substituent that comprisesreacting the corresponding compound having a 21-diazonium groupsubstituent with an acid in the substantial absence of water.

21. Method of preparing therapeutically useful substances of thesaturated and unsaturated pregnane series that comprises reacting asubstance of said series having a 3-position hydroxyl substituent and a21-position diazonium group substituent With an agent containing areactive carbonyl group in the presence of a metallic alcoholate, andthereafter destroying the diazonium group of the reaction product in anacid reagent whereby the corresponding acid derivative is obtained.

TADEUS REICI-ISTEIN.

